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Metformin and Nelfinavir in Treating Patients With Relapsed and/or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03829020
Recruitment Status : Not yet recruiting
First Posted : February 4, 2019
Last Update Posted : February 4, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase I trial studies the side effects and best dose of metformin and nelfinavir in treating patients with multiple myeloma that has come back or does not respond to treatment. Metformin may stop the growth of tumor cells by disrupting the energy source within multiple myeloma cells. Nelfinavir may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving metformin and nelfinavir may work better in treating patients with multiple myeloma.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Drug: Bortezomib Drug: Metformin Hydrochloride Drug: Nelfinavir Mesylate Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the maximum tolerated dose (MTD) of administering metformin hydrochloride (metformin) in combination with nelfinavir mesylate (nelfinavir) in patients with relapsed/refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. To describe the safety and tolerability of metformin in combination with nelfinavir in patients with relapsed/refractory multiple myeloma.

II. To assess the best hematological response of the combination of metformin and nelfinavir within 6 cycles of initiating therapy.

EXPLORATORY OBJECTIVES:

I. To describe the safety and tolerability of adding bortezomib to the combination of metformin and nelfinavir.

II. To describe any depth of hematological response obtained after adding bortezomib to the combination of metformin and nelfinavir.

III. Assess clinical biomarkers predictive of response to the combination of metformin and nelfinavir with or without the addition of bortezomib such as bioenergetic profiles of the myeloma cells, GLUT4 expression on myeloma cells, PI3K/AKT/mTOR and MAPK signaling pathways and metabolomics-based profiling.

OUTLINE: This is a dose-escalation study.

Patients receive metformin hydrochloride orally (PO) on days 1-21 of cycle 1 and days 1-14 of cycles 2-6. Patients also receive nelfinavir mesylate PO on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease (PD) at any time within 5 cycles or no minimal response (unconfirmed [u]MR or MR) after 2 cycles or no partial response (uPR or PR) after 4 cycles also receive bortezomib subcutaneously (SC) once weekly every 21 days in the absence of disease progression or unacceptable toxicity.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Phase 1 Study of Metformin in Combination With Nelfinavir in Patients With Relapsed and/or Refractory Multiple Myeloma
Estimated Study Start Date : March 1, 2019
Estimated Primary Completion Date : August 21, 2021
Estimated Study Completion Date : August 21, 2021


Arm Intervention/treatment
Experimental: Treatment (metformin, nelfinavir)
Patients receive metformin hydrochloride PO on days 1-21 of cycle 1 and days 1-14 of cycles 2-6. Patients also receive nelfinavir mesylate PO on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with PD at any time within 5 cycles or no uMR or MR after 2 cycles or no uPR or PR after 4 cycles also receive bortezomib SC once weekly every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Bortezomib
Given SC
Other Names:
  • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
  • LDP 341
  • MLN341
  • PS-341
  • PS341
  • Velcade

Drug: Metformin Hydrochloride
Given PO
Other Names:
  • APO-Metformin
  • Cidophage
  • Dimefor
  • Glifage
  • Glucoformin
  • Glucophage
  • Glucophage ER
  • Metformin HCl
  • Riomet
  • Siofor

Drug: Nelfinavir Mesylate
Given PO
Other Names:
  • AG1343
  • Viracept




Primary Outcome Measures :
  1. Maximum tolerated dose of the combination of metformin and nelfinavir [ Time Frame: 42 days ]
    Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients).


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2.5 years ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

  2. Hematologic response rate [ Time Frame: Up to 2.5 years ]
    Defined to be a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) noted as the objective status on two consecutive evaluations. Exact binomial 95% confidence intervals for the true hematologic response rate will be calculated.


Other Outcome Measures:
  1. Incidence of adverse events [ Time Frame: Up to 2.5 years ]
    Adverse events will be evaluated and summarized separately for the cycles where patients are receiving bortezomib in addition to metformin and nelfinavir. Frequency tables will be reviewed.

  2. Hematologic response [ Time Frame: Up to 2.5 years ]
    Will be assessed both before and after the addition of bortezomib in patients who add bortezomib for progressive disease or lack of response. Improvements in depth of response will be assessed and will be summarized descriptively.

  3. Clinical biomarker analysis [ Time Frame: Up to 2.5 years ]
    Will be explored and correlated with response to the combination of metformin and nelfinavir with or without the addition of bortezomib using Fisher?s exact and Wilcoxon rank sum tests. Clinical biomarkers examined may include bioenergetic profiles of the myeloma cells, GLUT4 expression on myeloma cells, PI3K/AKT/mTOR and MAPK signaling pathways and metabolomics-based profiling.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Actively relapsing multiple myeloma
  • Measurable disease of multiple myeloma as defined by at least ONE of the following:

    • Serum monoclonal protein >= 0.5 g/dL

      • If immunoglobulin A (IgA) isotype, then IgA quantification > upper limit of normal.
    • >= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
    • Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
    • Monoclonal bone marrow plasmacytosis >= 10% (evaluable disease)
  • Patients must have received at least 2 prior regimens and patients should have been exposed to a proteasome inhibitor (PI), an immunomodulatory drugs (IMiD) and an anti-CD38 antibody. NOTE: Induction therapy followed by an autologous stem cell transplant (ASCT) and maintenance therapy without any relapse counts as 1 regimen
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to registration)
  • Platelet count >= 50,000/mm^3 or >= 30,000/mm^3 if bone marrow plasma cells percentage >= 50% by morphology (obtained =< 14 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration)
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement) (obtained =< 14 days prior to registration)
  • Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration)
  • Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only. NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Provide written informed consent
  • Able to swallow metformin and nelfinavir tablets
  • Willingness to provide mandatory blood sample and bone marrow aspirate for research purposes
  • Willingness to return to Mayo Clinic for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

  • The following populations should be excluded from study:

    • Pregnant persons
    • Nursing persons
    • Persons of childbearing potential who are unwilling to employ adequate contraception
  • Major surgery =< 14 days before study registration
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Another active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy. NOTE: Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria
  • History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Known allergy to any of the study medications, their analogues or excipients in the various formulations
  • Subjects must not have conditions associated with increased risk of metformin associated lactic acidosis, including New York Heart Association class III or IV congestive heart failure, history of acidosis of any type, alcoholic liver disease, or habitual intake of 3 or more alcoholic beverages per day
  • Clinical history of type I or type II diabetes
  • Currently on either metformin or a HIV-PI or both
  • Elevated baseline lactate level > ULN (2.3 mmol/L)
  • Any of the following recent prior anti-myeloma therapy:

    • Alkylators (e.g. melphalan, cyclophosphamide) and anthracyclines =< 14 days prior to registration
    • High dose corticosteroids (equivalent to > 10 mg of prednisone/day) and immunomodulatory drugs (thalidomide or lenalidomide) =< 7 days prior to registration
    • Monoclonal antibodies =< 14 days prior to registration
  • Currently receiving any of the medications that cannot be discontinued 7 days prior to starting study and throughout study therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03829020


Locations
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United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials I. Referral Office    855-776-0015      
Principal Investigator: Wilson I. Gonsalves         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Wilson Gonsalves Mayo Clinic

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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03829020     History of Changes
Other Study ID Numbers: MC1811
NCI-2019-00466 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1811 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: February 4, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Metformin
Bortezomib
Nelfinavir
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents